Acute vs. Delayed Iron: Effect on Red Cell Iron Incorporation in Severe Malaria

描述（由申请人提供）：每年约有100万生活在撒哈拉以南非洲的5岁以下儿童死于严重贫血。这种严重的贫血通常是由铁缺乏和疟疾感染并存引起的，但在一些研究中，铁疗法和抗疟疾治疗的标准治疗已被证明对治愈严重贫血无效，并促进了寄生虫的增殖。对抗疟疾的促炎免疫反应下调了肠道中的铁吸收，使得在疟疾感染期间提供口服铁补充剂的效用值得怀疑。本研究拟使用铁稳定同位素和随机设计来测试抗疟治疗后立即或4周后开始铁剂治疗是否与初始铁剂治疗时更多的铁掺入红细胞和改善长期血液学恢复相关。100名严重贫血（血红蛋白5-7.9 g/dL）的乌干达儿童，6-36个月，有疟疾的临床体征，在乌干达坎帕拉Mulago医院儿科急性护理病房就诊，将被随机分配在抗疟治疗后第0天（立即组）或4周后第28天（延迟组）立即开始铁剂治疗。儿童将于第0天、第28天和第56天在医院接受评估，并在56天研究期间接受每两周一次的家庭访视。所提出的研究的具体目标和相应的假设是：目标1：确定抗疟治疗和铁治疗的顺序，从而在以下条件下产生最大的红细胞铁掺入： 第一次补铁的时间。工作假设是，红细胞铁掺入将在儿童开始补充剂给药时更大， 与抗疟治疗同时开始铁剂治疗的儿童（立即组）相比，抗疟治疗后4周开始铁剂治疗（延迟组），由于更完全的寄生虫清除和炎症消退，允许更好的铁吸收，分布和利用。目的2：确定长期血液学恢复是否受到即时与延迟铁的影响。工作假设是，与立即治疗相比，延迟铁治疗将与第56天血红蛋白增加和铁状态改善相关，因为延迟组中寄生虫清除更完全，从而改善了铁的吸收和使用。这项研究的结果将建立一个基于生理学的框架，以确定抗疟治疗和铁剂治疗的最佳时机，在此基础上，可以建立旨在改善疟疾流行地区铁状况的未来干预措施，从而有助于降低发病率和死亡率，并确保数百万患有缺铁和疟疾的严重贫血儿童的神经行为全面发育。 公共卫生相关性：在撒哈拉以南非洲，缺铁和疟疾并存，经常导致严重贫血、认知障碍和5岁以下儿童死亡。本研究将使用稳定的铁同位素来确定是否首先治疗疟疾和相关炎症，并将铁治疗延迟四周，与目前的标准治疗相比，铁和抗疟治疗会导致更大的铁吸收。这项研究的结果将建立铁和抗疟治疗的最佳顺序，从而指导非洲和其他疟疾流行地区未来的铁和疟疾干预计划。

DESCRIPTION (provided by applicant): Approximately 1 million children < 5 y living in sub-Saharan Africa die from severe anemia annually. This severe anemia frequently results from coexisting iron deficiency and malaria infection, but the standard of care, concurrent iron therapy and antimalarial treatment, has proven ineffective at curing the profound anemia and has promoted proliferation of the parasite in some studies. The pro-inflammatory immune response mounted against malaria down-regulates iron absorption in the gut, making provision of oral iron supplements during malarial infection of questionable utility. The present study proposes to use iron stable isotopes and a randomized design to test whether starting 4 weeks of iron therapy immediately after antimalarial treatment or 4 weeks later is associated with greater iron incorporation into red blood cells at the time of initial administration of iron theray and improved long-term hematological recovery. One hundred severely anemic (hemoglobin 5-7.9 g/dL) Ugandan children 6-36 mos with clinical signs of malaria who present to the Pediatric Acute Care Ward of Mulago Hospital in Kampala, Uganda, will be randomized to start iron immediately after antimalarial treatment on Day 0 (immediate group) or 4 weeks later on Day 28 (delayed group). Children will be assessed at the hospital on Day 0, Day 28 and Day 56 and will receive bi-weekly home visits for the 56-day study duration. The specific aims and corresponding hypotheses of the proposed study are: Aim 1: Identify the sequencing of antimalarial treatment and iron therapy that results in the greatest red cell iron incorporation at the time of initial iron supplement administration. The working hypothesis is that red cell iron incorporation will be greater at the time of initial supplement administration in children starting iron 4 weeks after antimalarial treatment (delayed group) compared to children starting iron concurrently with antimalarial treatment (immediate group), due to more complete parasite clearance and resolution of inflammation, permitting better iron uptake, distribution, and utilization. Aim 2: Determine whether long-term hematological recovery is impacted by immediate vs. delayed iron. The working hypothesis is that delayed iron treatment will be associated with greater hemoglobin and improved iron status at Day 56 compared to immediate treatment due to more complete parasite clearance and consequent improved iron absorption and use in the delayed group. The results of this study will establish a physiologically-based framework for the optimal timing of antimalarial treatment and iron therapy upon which future interventions aimed at improving iron status in malaria-endemic regions can be built, thus helping to reduce the morbidity and mortality and ensure the full neurobehavioral development of the millions of severely anemic children suffering from iron-deficiency and malaria. PUBLIC HEALTH RELEVANCE: Iron deficiency and malaria coexist in sub-Saharan Africa and frequently lead to severe anemia, cognitive impairment, and mortality among children < 5 y. The present study will use stable iron isotopes to determine whether treating malaria and associated inflammation first, and delaying iron therapy by four weeks, results in greater iron absorption compared to concurrent iron and antimalarial treatment, the current standard of care. The results of this study will establish the optimum sequencing of iron and antimalarial treatment, thus guiding future iron and malaria intervention programs in Africa and other malaria-endemic regions.